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Submitted on July 19, 2006
Accepted on September 5, 2006
-Casein Gene in Mammary Epithelial Cells
Department of Pathology, Program in Molecular Biology,and Dept of Microbiology,University of Colorado Health Sciences Center, Aurora, CO 80045. Baylor College of Medicine,Department of Molecular and Cellular Biology, Houston, TX 77030. Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck A-6020, Austria
* To whom correspondence should be addressed. E-mail: deane{at}bcm.tmc.edu.
Prolactin (PRL) and glucocorticoids act synergistically to stimulate transcription of the 
-casein milk protein gene. Signal transducer and activator of transcription 5 (Stat5) mediates PRL-dependent trans-activation and glucocorticoid potentiation occurs through cross-talk between glucocorticoid receptor (GR) and Stat5 at the -casein promoter. In the mouse, progesterone withdrawal leads to terminal differentiation and secretory activation of the mammary gland at parturition, indicating progesterone'Os role in repressing milk protein gene expression during pregnancy. To investigate the mechanism of the inhibitory action of progesterone, experiments were performed with cell culture systems reconstituted to express progesterone receptor (PR), the PRL receptor/Stat5 signaling pathway and GR, enabling evaluation of PR, GR and Stat5 interactions at the -casein promoter. With COS-1, NMuMG, HC-11 and primary mammary epithelial cells, progestin-PR directly repressed the PRLR/Stat5a signaling pathway'Os mediation of PRL induced -casein transcription. Progestin-PR also inhibited glucocorticoid-GR enhancement of PRL induced trans-activation of -casein. Inhibition depended on a functional PR DNA binding domain and specific PR-DNA interactions at the -casein promoter. Chromatin immunoprecipitation (ChIP) assays in HC-11 cells revealed recruitment of PR and Stat5a to the -casein promoter by progestin or PRL, respectively. Recruitment was disrupted by co-treatment with progestin and PRL, suggesting a mutual interference between activated PR and Stat5a. Without PRL, progestin-PR also recruited Stat5a to the -casein promoter, suggesting that recruitment of an unactivated form of Stat5a may contribute to inhibition of -casein by progesterone. These results define a negative cross-talk between PR and Stat5a/GR that may contribute to the physiologic role of progesterone to repress lactogenic hormone induction of the -casein gene in the mammary gland during pregnancy.
casein •
mammary gland •
gene repression
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